This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. This proposal continues ten years of work on biobehavioral monitoring methods with proven utility to the assessment of Type 1 Diabetes Mellitus (T1DM) by investigating from a systems biology point of view: (i) functional mechanisms triggering and accompanying hypoglycemia, and (ii) feedback mechanisms related to recurrent hypoglycemia, including microvascular physiology of increased insulin sensitivity and temporal patterns of impaired counter-regulation. Consequently, the proposed research plan includes GCRC-based investigations of the internal feedback loops of insulin transfer (Phase 2) and counter-regulation (Phase 3). Specifically: Phase 2 will investigate hypoglycemia and its relationship to microvascular and network dynamics of insulin transfer. We plan to assess the time course of insulin transfer from circulation to interstitium in subjects at low or high risk of hypoglycemia as determined by their history of moderate or severe hypoglycemia. This approach will provide insight on the time course of capillary responses and will allow for a dynamic quantitative assessment of the interstitial concentrations of insulin and glucose that are otherwise extremely difficult to measure even at isolated points in time and are certainly inaccessible as a dynamic process. Phase 3 will use a dynamic network model to investigate the time course of development and the dynamic characteristics of hypoglycemia-associated autonomic failure in T1DM subjects at low vs. high risk for hypoglycemia. In combination, the results from Phases 2 and 3 will clarify the relative contribution of counter-regulatory impairment and individual insulin sensitivity to occurrence of severe hypoglycemia. Subjects at high risk for severe hypoglycemia will experience a combination of higher insulin sensitivity and faster autonomic failure compared with subjects at low risk.